RE-ALIGN: Dabigatran in Patients With a Mechanical Heart Valve - PowerPoint PPT Presentation

RE-ALIGN: Dabigatran in Patients With a Mechanical Heart Valve Randomized, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacemeNt

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Background • Vitamin K antagonists provide effective protection against thrombosis in patients with a mechanical valve but require food, alcohol and drug restrictions and coagulation monitoring • Dabigatran 150 mg bid is superior to warfarin in non-valvular atrial fibrillation (RELY) • Encouraging preclinical data with dabigatran in porcine mechanical valve models 3

Study design of RE-ALIGN Study treatment Start warfarin up Warfarin to day 7 (INR according to guidelines) Population A 1 week follow-up or CrCl < 70 mL/min: transition to DE 150 mg bid RE-ALIGN extension CrCl 70 – < 110 mL/min: trial Population B DE 220 mg bid CrCl • 110 mL/min: DE 300 mg bid Start DE day 3–7 B: Surgery A: Surgery 12 weeks (> 3 months) Increase dose if dabigatran trough plasma level < 50 ng/mL (by Hemoclot  ) • • Discontinue dabigatran (switch to nonstudy VKA ) if < 50 ng/mL with 300 mg bid after 2 measurements 4

Adjudicated efficacy outcomes Population A Population B All patients Dabigatran Warfarin Dabigatran Warfarin Dabigatran Warfarin (n = 133) (n = 66) (n = 35) (n = 18) (n = 168) (n = 84) Death, n (%) 1 (1) 2 (3) 0 0 1 (1) 2 (2) Stroke, n (%) 9 (7) 0 0 0 9 (5) 0 SE, n (%) 0 0 0 0 0 0 TIA, n (%) 2 (2) 2 (3) 1 (3) 0 3 (2) 2 (2) MI, n (%) 1 (1) 0 2 (6) 0 3 (2) 0 Valve thrombosis 2 (2) 0 3 (9) 0 5 (3) 0 without symptoms Death/stroke/SE/ 11 (8) 2 (3) 2 (6) 0 13 (8) 2 (2) MI, n (%) Death/stroke/TIA/ 12 (9) 4 (6) 3 (9) 0 15 (9) 4 (5) SE/MI, n (%) 5 MI, myocardial infarction; SE, systemic embolism; TIA, transient ischaemic attack

Adjudicated safety outcomes Population A Population B All patients Dabigatran Warfarin Dabigatran Warfarin Dabigatran Warfarin (n = 133) (n = 66) (n = 35) (n = 18) (n = 168) (n = 84) Major bleeding, 7 (5) 2 (3) 0 0 7 (4) 2 (2) n (%) Major bleeding 7 (5) 2 (3) 0 0 7 (4) 2 (2) with pericardial location, n (%) Any bleeding, 35 (26) 8 (12) 10 (29) 2 (11) 45 (27) 10 (12) n (%) 6

Possible explanations for negative study results • Inadequate blood levels of dabigatran • Play of chance with relatively few events seen in the warfarin arm • Differences in the mechanism of action of dabigatran compared with warfarin • e.g., the inability of dabigatran to suppress activation of coagulation that occurs when blood is exposed to the artificial surface of prosthetic valves 7

Prosthetic valves and contact activation Dabigatran vs. Warfarin Contact Injury Extrinsic Intrinsic IXa/VIIIa TF/VIIa Tenase Tenase X X Xa Prothrombinase Warfarin Thrombin Dabigatran Clot formation 8

NEJM, September 1st, 2013 9